The cardioprotective and DNA topoisomerase II inhibitory agent dexrazoxane(ICRF-187) antagonizes camptothecin-mediated growth inhibition of Chinese hamster ovary cells by inhibition of DNA synthesis

Dexrazoxane (ICRF-187), which is clinically used to reduce doxorubicin-indu ced cardiotoxicity, has cell growth inhibitory properties through its abili ty to inhibit the catalytic activity of DNA topoisomerase II. A study was u ndertaken to investigate whether preincubating Chinese hamster ovary cells (CHO) with dexrazoxane prior to camptothecin treatment resulted in potentia tion. Camptothecin is a DNA topoisomerase I poison. It was found that pretr eating CHO cells with concentrations of dexrazoxane sufficient to strongly inhibit topoisomerase II for periods from 18 to 96 h resulted in significan t antagonism of camptothecin-mediated growth inhibition. Lower concentratio ns that were sufficient to cause partial inhibition of topoisomerase II and partial dexrazoxane-mediated cell growth inhibition had little effect on c amptothecin-mediated growth inhibition. Neither topoisomerase I protein lev els nor camptothecin-induced topoisomerase I-DNA covalent complexes were af fected by dexrazoxane concentrations that were sufficient to cause antagoni sm of camptothecin-induced growth inhibition. However, under these experime ntal conditions, dexrazoxane caused a decrease in DNA synthesis. Therefore, results presented here confirm the importance of the DNA synthesis-depende nt replication fork interaction with topoisomerase I-DNA covalent complexes for the expression of camptothecin activity. It is concluded that dexrazox ane and camptothecin analogs should be used with caution in combination che motherapy. [(C) 1999 Lippincott Williams & Wilkins.]